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Structural basis for featuring of steroid isomerase activity in alpha class glutathione transferases.

Tars K, Olin B, Mannervik B
J Mol Biol 397 332-40 (2010)
Related entries: 2vct, 2vcv

Cited: 24 times
EuropePMC logo PMID: 20083122

Abstract

Glutathione transferases (GSTs) are abundant enzymes catalyzing the conjugation of hydrophobic toxic substrates with glutathione. In addition to detoxication, human GST A3-3 displays prominent steroid double-bond isomerase activity; e.g. transforming Delta(5)-androstene-3-17-dione into Delta(4)-androstene-3-17-dione (AD). This chemical transformation is a crucial step in the biosynthesis of steroids, such as testosterone and progesterone. In contrast to GST A3-3, the homologous GST A2-2 does not show significant steroid isomerase activity. We have solved the 3D structures of human GSTs A2-2 and A3-3 in complex with AD. In the GST A3-3 crystal structure, AD was bound in an orientation suitable for the glutathione (GSH)-mediated catalysis to occur. In GST A2-2, however, AD was bound in a completely different orientation with its reactive double bond distant from the GSH-binding site. The structures illustrate how a few amino acid substitutions in the active site spectacularly alter the binding mode of the steroid substrate in relation to the conserved catalytic groups and an essentially fixed polypeptide chain conformation. Furthermore, AD did not bind to the GST A2-2-GSH complex. Altogether, these results provide a first-time structural insight into the steroid isomerase activity of any GST and explain the 5000-fold difference in catalytic efficiency between GSTs A2-2 and A3-3. More generally, the structures illustrate how dramatic diversification of functional properties can arise via minimal structural alterations. We suggest a novel structure-based mechanism of the steroid isomerization reaction.

Articles - 2wju mentioned but not cited (4)

  1. The impact of nitric oxide toxicity on the evolution of the glutathione transferase superfamily: a proposal for an evolutionary driving force. Bocedi A, Fabrini R, Farrotti A, Stella L, Ketterman AJ, Pedersen JZ, Allocati N, Lau PC, Grosse S, Eltis LD, Ruzzini A, Edwards TE, Morici L, Del Grosso E, Guidoni L, Bovi D, Lo Bello M, Federici G, Parker MW, Board PG, Ricci G. J Biol Chem 288 24936-24947 (2013)
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Reviews citing this publication (7)

  1. Glutathione catalysis and the reaction mechanisms of glutathione-dependent enzymes. Deponte M. Biochim Biophys Acta 1830 3217-3266 (2013)
  2. Glutathione transferases, regulators of cellular metabolism and physiology. Board PG, Menon D. Biochim Biophys Acta 1830 3267-3288 (2013)
  3. Glutathione Transferases: Potential Targets to Overcome Chemoresistance in Solid Tumors. Pljesa-Ercegovac M, Savic-Radojevic A, Matic M, Coric V, Djukic T, Radic T, Simic T. Int J Mol Sci 19 E3785 (2018)
  4. Recent advances in protein engineering and biotechnological applications of glutathione transferases. Perperopoulou F, Pouliou F, Labrou NE. Crit Rev Biotechnol 38 511-528 (2018)
  5. Glutathione S-transferases and their implications in the lung diseases asthma and chronic obstructive pulmonary disease: Early life susceptibility? van de Wetering C, Elko E, Berg M, Schiffers CHJ, Stylianidis V, van den Berge M, Nawijn MC, Wouters EFM, Janssen-Heininger YMW, Reynaert NL. Redox Biol 43 101995 (2021)
  6. Glutathione Transferases as Efficient Ketosteroid Isomerases. Mannervik B, Ismail A, Lindström H, Sjödin B, Ing NH. Front Mol Biosci 8 765970 (2021)
  7. The quest for molecular quasi-species in ligand-activity space and its application to directed enzyme evolution. Mannervik B, Runarsdottir A. FEBS Lett 584 2565-2571 (2010)

Articles citing this publication (13)

  1. A Halloween gene noppera-bo encodes a glutathione S-transferase essential for ecdysteroid biosynthesis via regulating the behaviour of cholesterol in Drosophila. Enya S, Ameku T, Igarashi F, Iga M, Kataoka H, Shinoda T, Niwa R. Sci Rep 4 6586 (2014)
  2. DeepDrug3D: Classification of ligand-binding pockets in proteins with a convolutional neural network. Pu L, Govindaraj RG, Lemoine JM, Wu HC, Brylinski M. PLoS Comput Biol 15 e1006718 (2019)
  3. Technical-grade perfluorooctane sulfonate alters the expression of more transcripts in cultured chicken embryonic hepatocytes than linear perfluorooctane sulfonate. O'Brien JM, Austin AJ, Williams A, Yauk CL, Yauk CL, Crump D, Kennedy SW. Environ Toxicol Chem 30 2846-2859 (2011)
  4. Porcine glutathione transferase Alpha 2-2 is a human GST A3-3 analogue that catalyses steroid double-bond isomerization. Fedulova N, Raffalli-Mathieu F, Mannervik B. Biochem J 431 159-167 (2010)
  5. Comparison of epsilon- and delta-class glutathione S-transferases: the crystal structures of the glutathione S-transferases DmGSTE6 and DmGSTE7 from Drosophila melanogaster. Scian M, Le Trong I, Mazari AM, Mannervik B, Atkins WM, Stenkamp RE. Acta Crystallogr D Biol Crystallogr 71 2089-2098 (2015)
  6. Isomerization of the phytohormone precursor 12-oxophytodienoic acid (OPDA) in the insect gut: a mechanistic and computational study. Dabrowska P, Shabab M, Brandt W, Vogel H, Boland W. J Biol Chem 286 22348-22354 (2011)
  7. Characterization of porcine alpha-class glutathione transferase A1-1. Fedulova N, Raffalli-Mathieu F, Mannervik B. Arch Biochem Biophys 507 205-211 (2011)
  8. Evolution of GSTD1 in Cactophilic Drosophila. López-Olmos K, Markow TA, Machado CA. J Mol Evol 84 285-294 (2017)
  9. Marmoset glutathione transferases with ketosteroid isomerase activity. Ismail A, Sawmi J, Mannervik B. Biochem Biophys Rep 27 101078 (2021)
  10. The effects of mutating Tyr9 and Arg15 on the structure, stability, conformational dynamics and mechanism of GSTA3-3. Robertson GJ, Stoychev SH, Sayed Y, Achilonu I, Dirr HW. Biophys Chem 224 40-48 (2017)
  11. Structural Effects of pH Variation and Calcium Amount on the Microencapsulation of Glutathione in Alginate Polymers. Bustos D, Hernández-Rodríguez EW, Castro RI, Morales-Quintana L. Biomed Res Int 2022 5576090 (2022)
  12. The isomerization of Δ5-androstene-3,17-dione by the human glutathione transferase A3-3 proceeds via a conjugated heteroannular diene intermediate. Daka JL, Achilonu I, Dirr HW. J Biol Chem 289 32243-32252 (2014)
  13. Conservation of Glutathione Transferase mRNA and Protein Sequences Similar to Human and Horse Alpha Class GST A3-3 across Dog, Goat, and Opossum Species. Hubert SM, Samollow PB, Lindström H, Mannervik B, Ing NH. Biomolecules 13 1420 (2023)


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